Targeting the TCR complex on human T-cells with anti-CD3 monoclonal antibodies has been used or suggested for treatment of autoimmune disease and related disorders such as in the treatment of organ allograft rejection. Mouse monoclonal antibodies specific for human CD3, such as OKT3 (Kung et al. (1979) Science 206: 347-9), were the first generation of such treatments. Although OKT3 has strong immunosuppressive potency, its clinical use was hampered by serious side effects linked to its immunogenic and mitogenic potentials (Chatenoud (2003) Nature Reviews 3:123-132). It induced an anti-globulin response, promoting its own rapid clearance and neutralization (Chatenoud et al. (1982) Eur. J. Immunol. 137:830-8). In addition, OKT3 induced T-cell proliferation and cytokine production in vitro and led to a large scale release of cytokine in vivo (Hirsch et al. (1989) J. Immunol 142: 737-43, 1989). The cytokine release (also referred to as “cytokine storm”) in turn led to a “flu-like” syndrome, characterized by fever, chills, headaches, nausea, vomiting, diarrhea, respiratory distress, septic meningitis and hypotension (Chatenoud, 2003). Such serious side effects limited the more widespread use of OKT3 in transplantation as well as the extension of its use to other clinical fields such as autoimmunity (Id.).
To reduce the side effects of the first generation of anti-CD3 monoclonal antibodies, a second generation of genetically engineered anti-CD3 monoclonal antibodies had been developed not only by grafting complementarity-determining regions (CDRs) of murine anti-CD3 monoclonal antibodies into human IgG sequences, but also by introducing non-FcR-binding mutations into the Fc to reduce occurrence of cytokine storm (Cole et al. (1999) Transplantation 68: 563; Cole et al. (1997) J. Immunol. 159: 3613). See also PCT Publication No. WO2010/042904 which is herein incorporated by reference in its entirety.
In addition to monospecific therapeutics that target CD3, multispecific polypeptides that bind selectively to T-cells and tumor cells could offer a mechanism to redirect T-cell cytotoxicity towards the tumor cells and treatment of cancer. One problem, however, to designing a bispecific or multispecific T-cell-recruiting antibody has been to maintain specificity while simultaneously overriding the regulation of T-cell activation by multiple regulatory pathways.
A need remains for improved anti-CD3 monospecific and multispecific molecules. Although previous improvements have been made in the Fc portion of CD3 targeting molecules to reduce the likelihood of cytokine storm, there is still a need for anti-CD3 therapeutics that have an increased half-life over prior art molecules, can be effectively manufactured, exhibit improved T-cell binding and/or improved redirected T-cell cytoxicity (in the case of multispecific molecules designed for treatment of cancer).